US4791215A - Derivatives of glutamic acid and aspartic acid - Google Patents
Derivatives of glutamic acid and aspartic acid Download PDFInfo
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- US4791215A US4791215A US06/746,065 US74606585A US4791215A US 4791215 A US4791215 A US 4791215A US 74606585 A US74606585 A US 74606585A US 4791215 A US4791215 A US 4791215A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/66—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
Definitions
- the invention relates to new derivatives of D,L-glutamic acid and D,L-aspartic acid that have antagonistic activity toward exogenous or endogenous bioactive polypeptides.
- the present invention relates to new derivatives of D,L-glutamic acid and D,L-aspartic acid having the formulae: ##STR2## in which n is equal to 1 or 2, R 1 is a phenyl group mono-, di- or tri-substituted with linear or branched C 1 -C 4 alkyl groups, which may be the same or different, or with halogens, with a cyano group or a trifluoromethyl group, and in which R 2 is selected from the group consisting of morpholino, piperidino and amino with one or two linear, branched or cyclic alkyl group substituents containing from 1 to 8 carbon atoms, which may be the same or different, or a pharmaceutically-acceptable salt thereof.
- the compounds have an antagonistic activity towards bioactive polypeptides and are useful particularly in the treatment of illnesses of the digestive system and the central nervous system, as pain killers, and for the treatment of anorexia and those affections in which exogenous or endogenous bioactive polypeptides are involved.
- the present invention relates to original derivatives of D,L-glutamic acid and D,L-aspartic acid which may be represented by the general formulae indicated below: ##STR3## in which n is equal to 1 or 2, R 1 is a phenyl group mono-, di- or tri-substituted with linear or branched C 1 -C 4 alkyl groups, which may be the same or different, or with halogens, with a cyano group or a trifluoromethyl group, and in which R 2 is selected from the group consisting of morpholino, piperidino and amino with one or two linear, branched or cyclic alkyl group substituents containing from 1 to 8 carbon atoms, which may be the same or different.
- the compounds which are the subject of the present invention have been shown to possess interesting pharmocological properties with regard to mammals.
- One of these properties is a capacity to potentiate the analgesic activity of morphine and other analgesic drugs.
- CCK cholecystokinin
- the compounds according to the invention may thus be used, to advantage, in the treatment of various human illnesses, such as illnesses of the digestive system, such as, for example, in the treatment of colitis and and biliary diskinesia; or may be used for the treatment of pain of any etiology and intensity.
- the compounds of the invention have a powerful anti-CCK activity on various experimental models, both in vitro and in vivo. Thus they reduce contractions induced by CCK in the gall bladder of guinea pigs both in vitro and in vivo, they inhibit induced contractions of the colon in rabbits, and they increase biliary secretion in rats.
- This potentiation of the activity of analgesic drugs is, among other things, correlated with the capacity of the compounds according to the invention to block the hydrolytic degradation of enkephalins, endogenous physiological peptides having powerful analgesic activities. This would give the enkephalins themselves a greater half-life and, by definition, a greater activity.
- compositions of the invention may be prepared by conventional methods as, for example, tablets, capsules, suspensions, solutions and suppositories, and may be administered orally, parenterally or via the rectum.
- the active ingredient is administered to the patient typically in quantities of from 0.1 to 10 mg/kg body weight per dose.
- a water-soluble salt of the compounds in question such as the sodium salt or another non-toxic, pharmaceutically-acceptable salt.
- Substances commonly used in the pharmaceutical industry as excipients, binders, flavouring agents, dispersants, colouring agents, humectants etc. may be used as inactive ingredients.
- the temperature of the reaction is from -10° C. to 10° C.
- the internal anhydrides (II) are made by the steps of:
- the series of steps of the method according to the invention is illustrated in its entirety in the reaction scheme below: ##STR6##
- the acylation step (b) is preferably carried out at a temperature of from 0° C. to 15° C. for a period of from 1 to 24 hours, a temperature of about 5° C. and a reaction time of 12 hours is to be recommended.
- step (c) the reaction time is typically from about 30 minutes to 12 hours, preferably about 3 hours, and the quantity of acetic anhydride is preferably 3 moles per mole of compound (III).
- the amine of formula R 2 H is preferably introduced in a molar ratio of 2.5 to 1 with respect to the internal anhydride (II) and the reaction is carried out for a period of from about 30 minutes to 12 hours, preferably 3 hours.
- the isomers IA and IB may be separated either by fractional crystallisation (with the solvents indicated in Tables (C) and (D) or by extraction in a basic medium, the compounds of formula IB being on average more acid.
- 30.2 g (0.1 moles) of 3,4-dichloro-benzoyl-glutamic anhydride are loaded into a reactor and suspended in 100 ml of water. The mass is cooled to about 5° C. and 32.2 g (0.25 moles) of di-n-butylamine are added dropwise over a period of about 15 minutes.
- the mixture is left to react for 3 hours at this temperature and acidified with glacial acetic acid. It is filtered, washed with water until it is neutral and dried.
- analgesic activity displayed by the compounds which are the subject of the invention will now be illustrated by a series of pharmacological tests arranged to demonstrate both their potentiation of the analgesic activity of opiates and the mechanism by which this potentiation is achieved.
- Male rats are used having a weight of about 150-200 g which have not fasted. A point on the tail is chosen and irradiated by a heat source (75° C.) and the time (in seconds) for which the animal remains without moving its tail is measured.
- a maximum period of time of 8 seconds under the heat source is chosen, after which the animal is, in any case, removed to avoid tissue damage.
- the measurement is effected before (controls) and after treatment with the drugs.
- the administration of the drugs which are the subject of the invention is carried out intraperitoneally (10 mg/kg) 10 minutes and immediately before administration of morphine (2 mg/kg).
- the percentage variation is calculated for each individual animal by the following formula: ##EQU1## The measurements were carried out 10, 20, 30, 45, 60 and 90 minutes after treatment with the analgesics.
- Table 1 which records the groups treated and the doses administered, the average percentage variations (calculated for groups of 5 animals) of the latency of the pain sensation, the average values calculated for the period 1-90 minutes ( ⁇ S.E.) and the potency ratio of the morpholine administered alone or together with the compounds which are the subject of the present invention.
- Groups of five male rats having a weight of about 150 g, and which have not fasted, are used.
- the animals are placed on a metal plate on the bottom of a transparent cylinder, which is heated to 55° ⁇ 1° C. by an azeotropic boiling mixture (acetone-ethyl formate 1:1).
- the reaction time is defined as the interval which passes between the moment at which the animal is placed on the hot-plate and the moment at which it either licks its feet or tries to jump out of the cylinder.
- the control reaction time is measured 10 and 5 minutes before administration of the drugs and 10, 20, 30, 45, 60 and 90 minutes afterwards. The animals are left on the plate for a maximum period of 30 seconds.
- the response to the administration of the product is considered positive if at least a doubling of the normal reaction time is seen.
- the results obtained are given in Tables 2a and 2b which record the groups treated, the doses administered and the stay times on the plate expressed as the number of positive responses over the number treated.
- the method is that described by Lewis et al. J. Neurosc. 1, 358 (1961). Male rats which have not fasted and have a weight of about 200 g are used.
- the animals are stressed by the application of a 60 Hz-2.5 mA current to the front leg in pulses of a duration of 1 second every 5 seconds for 20 minutes.
- the compounds are administered i.v. immediately before the electric shock at the doses indicated in Table 3.
- the compounds of the invention can increase the analgesic activity of endogenous enkephalins generally to a highly significant extent: this increase is dose-dependent, the effect in fact increasing in both intensity and duration in dependence on the dose.
- a cannula was implanted in the right lateral ventricle of male rats having a weight of 150-200 g (groups of five animals were used) in order to allow the intracerebroventricular (i.c.v.) administration of drugs according to the method of Noble et al (Life Science 6, (1970) 281-191).
- This activity which is highly significant even at doses of 0.01 ⁇ g/kg, is probably related to an inhibiting activity on an enzyme (or enzymes) responsible for the metabolism of the enkephalins.
- Experiment No. 5 Antagonism of several products of the invention to the development of tolerance induced in rats by the repeated administration of morphine HCl.
- each animal except the control group treated physiologically received 5 mg/kg of morphine hydrochloride i.p. together with 10 mg/kg i.p. of the compounds indicated (with the exception of the group treated solely with morphine).
- the determination of the pain threshold was effected 15', 30', 45' and 60' from the treatment by the Tail Flick Test.
- the data given in Table 5 relate to the average values of these four determinations and indicate the percentage variations in the latency time (appearance of pain) before and after treatment with the drugs.
- the table also gives the values of Student's t determined at various times for the groups treated with the drugs in comparison with the control group and the group treated with morphine.
- the morphine group was not significantly different from the control group, while the groups C-G maintained significant activity compared with the controls up to the final treatment after 168 hours.
- a longitudinal strip of guinea pig gall bladder was placed in a bath of isolated members in the presence of Krebs at a temperature of 32° C. with continuous oxygenation with an oxygen-CO 2 mixture (95-5V/V).
- the isometric contractions were detected by means of a force transducer and recorded.
- the gall bladder was made to contract with the use of a 10 ng/ml concentration of CCK-8; the antagonistic activity of the compounds of the invention on the contracting effect of the CCK was determined with the use of different concentrations and the ED 50 value, that is the concentration in ⁇ g/ml of a compound which could antagonise 50% of the contracting effect of the CCK, was determined.
- the responses of the gall bladders to the substances under test were detected by means of a force transducer and recorded by means of a microdynamometer.
- the optimum contracting dose was chosen as 10 ng/kg of CCK-8.
- the antagonist compounds tested were administered in increasing doses so as to enable the calculation of an ED50 value, that is in the dose (in mg/kg i.v.) capable of inhibiting 50% of the contracting effect of 10 ng/kg i.v. of CCK-8.
- mice with the vegetable carbon test rate of transit through the stomach and the intestine
- the abdomen of an anaesthetised rabbit was cut open to show the transverse colon.
- a small balloon full of water was inserted at the point established and connected to a pressure transducer by means of a polythene cannula filled with water.
- the anti-spastic activity is shown at very low doses of between 1-3 mg/kg for the best of the compounds used.
- a cannula was inserted in the bile duct of a rat anaesthetised with urethane, together with a small needle connected to a polythene tube, and the bile liquid was thus collected.
- the collection was carried out for one hour before the intravenous administration of the tested compounds and for a further two hours after administration, the samples collected at 30 minute intervals being weighed.
- ED 50 that is the quantity of substance in mg/kg i.v. capable of causing a 50% increase in the biliary flow after the treatment with the drugs (average value determined over the 2 hour period) with respect to control values (average value determined during one hour of collection before the treatment with the drugs).
- the compounds in question have a powerful choleretic activity; on average the ED 50 for the compounds tested was 5-25 mg/kg i.v. and there was a remarkable correspondence between the dose and the pharmocological response (the coefficients of correlation were in fact greater than 0.90 in all cases).
- mice Male rats having a weight of about 160 g, divided into groups of 10 animals, were used. Each group was given the drug daily, in the doses indicated, for 3 weeks.
- the drug in the form of the sodium salt, was dissolved in water and administered in a volume of 10 ml of H 2 O/kg while the control group received an equal volume of the solvent alone.
- the anti-cholecystokinin effect of the most powerful of the compounds which are the subject of the present invention, that is the compound C-7, on the trophic activity of CCK on normal pancreatic cells and on those of a pancreatic adenocarcinoma is to be studied.
- mice Male hamsters were inoculated in the cheek pouches with a suspension of 1 ⁇ 10 5 tumoral cells of a pancreatic adenocarcinoma. Five days after the inoculation the animals were divided at random into 4 groups of 10 animals each, that is, a control group, a group of animals treated with 10 ⁇ g/kg of CCK-8 three times a day, a group of animals treated with 5 mg/kg i.p. of compound C-7 three times a day, and a fourth group treated simultaneously with the compound C-7 and CCK-8 in the manner described above.
- the data given in the table show that the cholecystokinin hormone (of which CCK-8 is the biologically active component), which has a trophic action on normal pancreatic cells, also stimulates the growth of a pancreatic adenocarcinoma.
- the compound C-7 a powerful specific CCK antagonist, antagonises both these actions of CCK-8 in a higly significant manner.
- morphine or other analgesic drugs is a considerable therapeutic innovation which can make available to the doctor compounds of pre-eminent interest for the treatment of pain of any etiology.
- This treatment would appear to be particularly indicated in the case of prolonged administrations of opiates where there is a very great need for the drug not to cause habituation, or at least for this to be maintained within acceptable limits.
- their possible use in the detoxication of patients who have become dependent from the prolonged use of opiate drugs would appear to be of enormous therapeutic and social interest.
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Abstract
Description
TABLE A __________________________________________________________________________ D,L-Nacyl derivatives of glutamic and aspartic acids: ##STR7## COM- MELTING SOLVENT OF YIELD POUNDS n R.sub.1 POINT (°C.) CRYSTALLIZATION Rf (%) FORMULA __________________________________________________________________________ A-1 2 2-chloro-phenyl 116-8 H.sub.2 O 0.32 76.5 C.sub.12 H.sub.12 ClNO.sub.5 1 A-2 2 3-chloro-phenyl 134-8 H.sub.2 O 0.40 80.3 C.sub.12 H.sub.12 ClNO.sub.5 . A-3 2 4-chloro-phenyl 105-7 H.sub.2 O 0.44 84.7 C.sub.12 H.sub.12 ClNO.sub.5 A-4 2 3,4-dichloro-phenyl 141-5 H.sub.2 O 0.46 76.4 C.sub.12 H.sub.11 Cl.sub.2 NO.sub.5 A-5 2 3,5-dichloro-phenyl 147-9 H.sub.2 O 0.48 90.1 C.sub.12 H.sub.11 Cl.sub.2 NO.sub.5 A-6 2 2,4-dichloro-phenyl 125-7 H.sub.2 O 0.43 58.5 C.sub.12 H.sub.11 Cl.sub.2 NO.sub.5 A-7 2 3,4,5-trichloro-phenyl 143-5 H.sub.2 O/alcohol 1:1 0.46 85.7 C.sub.12 H.sub.10 Cl.sub.3 NO.sub.5 A-8 1 3,4-dichloro-phenyl 158-61 H.sub.2 O 0.38 86.6 C.sub.11 H.sub.9 Cl.sub.2 NO.sub.5 A-9 2 4-fluoro-phenyl 84-86 -- 0.37 79.5 C.sub.12 H.sub.12 FNO.sub.5 A-10 2 3,5-difluoro-phenyl 148-51 H.sub.2 O 0.41 85.5 C.sub.12 H.sub.11 F.sub.2 NO.sub.5 A-11 2 2-bromo-phenyl 127-9 H.sub.2 O 0.33 93.1 C.sub.12 H.sub.12 BrNO.sub.5 A-12 2 4-bromo-phenyl 148-50 H.sub.2 O/alcohol 7:3 0.43 87.8 C.sub.12 H.sub.12 BrNO.sub.5 A-13 1 2-bromo-phenyl 147-9 H.sub.2 O 0.19 90.2 C.sub.11 H.sub.10 BrNO.sub.5 A-14 2 2-iodo-phenyl 135-8 H.sub.2 O 0.35 70.5 C.sub.12 H.sub.12 INO.sub.5 A-15 2 4-iodo-phenyl 171-3 H.sub.2 O/alcohol 7:3 0.47 84.8 C.sub.12 H.sub.12 INO.sub.5 A-16 2 3,4,5-triiodo-phenyl 180-4 H.sub.2 O/alcohol 1:1 0.53 87.0 C.sub.12 H.sub.10 I.sub.3 NO.sub.5 A-17 2 3-cyano-phenyl 123-6 H.sub.2 O 0.22 81.2 C.sub.13 H.sub.12 N.sub.2 O.sub.5 A-18 1 3-cyano-phenyl 175-9 H.sub.2 O 0.12 86.5 C.sub.12 H.sub.10 N.sub.2 O.sub.5 A-19 2 4-cyano-phenyl oil -- 0.27 71.0 C.sub.13 H.sub.12 N.sub.2 O.sub.5 A-20 2 3-methyl-phenyl 127-8 H.sub.2 O 0.33 80.0 C.sub.13 H.sub.15 NO.sub.5 A-21 2 4-methyl-phenyl 102-8 H.sub.2 O 0.34 95.0 C.sub.13 H.sub.15 NO.sub.5 A-22 2 3,4-dimethyl-phenyl 131-3 H.sub.2 O/alcohol 7:3 0.38 85.0 C.sub.14 H.sub.17 NO.sub.5 A-23 2 3,5-dimethyl-phenyl 153-5 H.sub.2 O/alcohol 7:3 0.41 83.5 C.sub.14 H.sub.17 NO.sub.5 A-24 2 2,4-dimethyl-phenyl 98-105 H.sub.2 O/alcohol 7:3 0.38 65.8 C.sub.14 H.sub.17 NO.sub.5 A-25 2 2,4,6-trimethyl-phenyl 170-4 H.sub.2 O/alcohol 7:3 0.43 72.0 C.sub.15 H.sub.19 NO.sub.5 A-26 2 4-ethyl-phenyl 154-6 H.sub.2 O/alcohol 7:3 0.38 88.6 C.sub.14 H.sub.17 NO.sub.5 A-27 2 4-n-propyl-phenyl 108-13 H.sub.2 O 0.41 82.3 C.sub.15 H.sub.19 NO.sub.5 A-28 2 4-isopropyl-phenyl 49-52 H.sub.2 O 0.37 50.8 C.sub.15 H.sub.19 NO.sub.5 A-29 2 4-n-butyl-phenyl oil -- 0.43 61.5 C.sub.16 H.sub.21 NO.sub.5 A-30 2 4-isobutyl-phenyl 118-25 H.sub.2 O 0.40 78.0 C.sub.16 H.sub.21 NO.sub.5 A-31 2 4-trifluoromethyl- 153-5 H.sub.2 O 0.30 79.0 C.sub.13 H.sub.12 F.sub.3 NO.sub.5 phenyl __________________________________________________________________________ (*) Eluent used: Chloroform-Acetic Acid -H.sub.2 O (8-2-0.1)
TABLE B __________________________________________________________________________ Derivatives of Nacyl-glutamic and aspartic anhydrides of formula: ##STR8## Melting point Yield COMPOUNDS n R.sub.1 (°C.) (%) FORMULA __________________________________________________________________________ B-1 2 2-chloro-phenyl 129-31 79.5 C.sub.12 H.sub.10 ClNO.sub.4 B-2 2 3-chloro-phenyl 157-8 83.8 C.sub.12 H.sub.10 ClNO.sub.4 B-3 2 4-chloro-phenyl 187-90 87.8 C.sub.12 H.sub.10 ClNO.sub.4 B-4 2 3,4-dichloro-phenyl 188-90 89.3 C.sub.12 H.sub.9 Cl.sub.2 NO.sub.4 B-5 2 3,5-dichloro-phenyl 214-16 74.7 C.sub.12 H.sub.8 Cl.sub.2 NO.sub.4 B-6 2 2,4-dichlorophenyl 155-7 74.2 C.sub.12 H.sub.9 Cl.sub.2 NO.sub.4 B-7 2 3,4,5-trichloro-phenyl 208-10 93.3 C.sub.12 H.sub.8 Cl.sub.3 NO.sub.4 B-8 1 3,4-dichloro-phenyl 195-7 91.4 C.sub.11 H.sub.7 Cl.sub.2 NO.sub.4 B-9 2 4-fluoro-phenyl 171-3 72.1 C.sub.12 H.sub.10 FNO.sub.4 B-10 2 3,5-difluoro-phenyl 198-203 91.2 C.sub.12 H.sub.9 F.sub.2 NO.sub.4 B-11 2 2-bromo-phenyl 147-9 72.8 C.sub.12 H.sub.10 BrNO.sub.4 B-12 2 4-bromo-phenyl 200-3 76.9 C.sub.12 H.sub.10 BrNO.sub.4 B-13 1 2-bromo-phenyl 161-4 84.1 C.sub.11 H.sub.8 BrNO.sub.4 B-14 2 2-iodo-phenyl 158-60 75.6 C.sub.12 H.sub.10 INO.sub.4 B-15 2 4-iodo-phenyl 201-3 88.0 C.sub.12 H.sub.10 INO.sub.4 B-16 2 3,4,5-triiodo-phenyl 225-8 85.2 C.sub.12 H.sub.8 I.sub.3 NO.sub.4 B-17 2 3-cyano-phenyl 171-3 76.7 C.sub.13 H.sub.10 N.sub.2 O.sub.4 B-18 1 3-cyano-phenyl 173-77 81.9 C.sub.12 H.sub.8 N.sub.4 O.sub.4 B-19 2 4-cyano-phenyl 181-5 78.8 C.sub.13 H.sub.10 N.sub.2 O.sub.4 B-20 2 3-methyl-phenyl 144-8 74.0 C.sub.13 H.sub.13 NO.sub.4 B-21 2 4-methyl-phenyl 188-90 74.2 C.sub.13 H.sub.13 NO.sub.4 B-22 2 3,4-dimethyl-phenyl 161-3 82.5 C.sub.14 H.sub.15 NO.sub.4 B-23 2 3,5-dimethyl-phenyl 155-7 69.0 C.sub.14 H.sub.15 NO.sub.4 B-24 2 2,4-dimethyl-phenyl 135-8 41.2 C.sub.14 H.sub.15 NO.sub.4 B-25 2 2,4,6-trimethyl-phenyl 160-5 38.8 C.sub.15 H.sub.17 NO.sub.4 B-26 2 4-ethyl-phenyl 174-6 78.0 C.sub.14 H.sub.15 NO.sub.14 B-27 2 4-n-propyl-phenyl 159-61 72.4 C.sub.15 H.sub.17 NO.sub.4 B-28 2 4-isopropyl-phenyl 153-5 64.5 C.sub.15 H.sub.17 NO.sub.4 B-29 2 4-n-butyl-phenyl 142-4 73.0 C.sub.16 H.sub.19 NO.sub.4 B-30 2 4-isobutyl-phenyl 139-43 72.8 C.sub.16 H.sub.19 NO.sub.4 B-31 2 4-trifluoromethyl-phenyl 157-9 79.0 C.sub.13 H.sub.10 F.sub.3 NO.sub.4 __________________________________________________________________________
TABLE C __________________________________________________________________________ Derivatives of formula: ##STR9## __________________________________________________________________________ COM- Melting Solvent of Yield POUNDS n R.sub.1 R.sub.2 Point (°C.) Crystallisation Rf (%) __________________________________________________________________________ C-1 2 2-chloro-phenyl di-n-propyl-amino 133-5 Ethyl acetate 0.78 53.5 C-2 2 3-chloro-phenyl di-n-propyl-amino 126-8 Acetone 0.80 17.0 C-3 2 4-chloro-phenyl di-n-propyl-amino 101-3 H.sub.2 O/Ethanol 3:7 0.88 50.0 C-4 2 4-chloro-phenyl di-n-pentyl-amino 104-7 H.sub.2 O/Ethanol 1:1 0.94 24.2 C-5 2 3,4-dichloro-phenyl di-n-propyl-amino 108-10 Ethyl acetate 0.87 28.0 C-6 2 3,4-dichloro-phenyl di-n-butyl-amino 81-3 Isopropyl ether 0.92 38.0 C-7 2 3,4-dichloro-phenyl di-n-pentyl-amion 106-8 Isopropyl ether 0.95 31.7 C-8 2 3,4-dichloro-phenyl di-n-hexyl-amino 108-10 Isopropyl ether 0.97 21.8 C-9 2 3,5-dichloro-phenyl di-n-butyl-amino 165-7 H.sub.2 O/Ethanol 1:4 0.95 53.4 C-10 2 2,4-dichloro-pehnyl di-n-butyl-amino 124-6 H.sub.2 O/Ethanol 1:2 0.92 57.6 C-11 2 3,4,5-trichloro-phenyl di-n-butyl-amino 132-4 H.sub.2 O/Ethano1 1:4 0.96 23.3 C-12 2 4-fluoro-phenyl di-n-propyl-amino 123-5 H.sub.2 O/Ethanol 1:1 0.85 43.5 C-13 2 3,5-difluoro-phenyl di-n-propyl-amino 132-6 H.sub.2 O/Ethanol 3:7 0.88 11.4 C-14 2 2-bromo-phenyl di-n-propyl-amino 132-3 H.sub.2 O/Ethanol 1:1 0.85 54.2 C-15 2 4-bromo-phenyl di-n-propyl-amino 129-31 Ethyl acetate 0.83 20.7 C-16 1 2-bromo-phenyl di-n-propyl-amino 123-4 Ethyl acetate 0.63 40.9 C-17 2 2-iodo-phenyl di-n-propyl-amino 146-8 Ethyl acetate 0.86 25.2 C-18 2 4-iodo-phenyl di-n-propyl-amino 104-11 Ethyl acetate 0.83 18.3 C-19 2 3,4,5-triiodo-phenyl di-n-propyl-amino 102-5 H.sub.2 O/Ethanol 1:1 0.88 27.6 C-20 2 3-cyano-phenyl di-n-propyl-amino 120-5 Ethyl acetate 0.78 37.0 C-21 2 3-cyano-phenyl n-butyl-amino 130-2 H.sub.2 O/Ethanol 1:1 0.75 28.4 C-22 1 3-cyano-phenyl di-n-propyl-amino 144-5 Ethyl acetate 0.63 20.0 C-23 1 3-cyano-phenyl ciclohexyl-amino 188-92 H.sub.2 O/Ethanol 3:2 0.69 90.7 C-24 2 3-cyano-phenyl di-n-butyl-amino 127-9 H.sub.2 O/Ethanol 1:1 0.82 54.8 C-25 2 4-bromo-phenyl di-n-butyl-amino 120-2 Isopropyl ether 0.92 27.0 C-26 2 3,4-dichloro-phenyl piperidino 183-5 Ethyl acetate 0.74 29.4 C-27 2 4-iodo-phenyl di-n-butyl-amino 86-92 H.sub.2 O/Ethanol 1:2 0.81 39.8 __________________________________________________________________________ COM- Melting Solvent for POUNDS n R.sub.1 R.sub.2 point (°C.) crystallisation RF(*) % Yield __________________________________________________________________________ C-28 2 3-methyl-phenyl di-n-propyl-amino 132--3 ethyl acetate 0.80 31.0 C-29 2 4-methyl-phenyl " 137-9 " 0.85 28.8 C-30 2 3,4-dimethyl-phenyl " 142-4 " 0.83 44.0 C-31 2 3,5-dimethyl-phenyl " 144-6 ethanol/water 3:2 0.89 23.4 C-32 2 2,4-dimethyl-phenyl " 127-9 ethyl acetate 0.84 50.4 C-33 2 2,4,6-trimethyl- " 166-8 " 0.89 39.5 phenyl C-34 2 4-ethyl-phenyl " 129-31 " 0.86 45.7 C-35 2 4-n-propyl-phenyl " 117-9 ethanol/water 1:1 0.82 38.3 C-36 2 4-isopropyl-phenyl " 147-150 methanol/water 7:3 0.91 48.0 C-37 2 4-n-butyl-phenyl " 126-8 methanol/water 3:1 0.79 34.7 C-38 2 4-isobutyl-phenyl " 137-41 methanol/water 7:3 0.85 24.5 C-39 2 4-trifluoromethyl- " 119-21 ethanol 0.76 37.6 phenyl C-40 2 3,4-dimethyl-phenyl di-ethyl-amino 191-2 ethanol 0.67 65.0 C-41 2 4-n-propyl-phenyl " 133-5 ethanol/water 1:1 0.63 46.4 C-42 2 3,4-dimethyl-phenyl n-butyl-amino 155-7 ethanol/water 7:3 0.68 21.4 C-43 2 4-ethyl-phenyl " 137-9 ethanol 95% 0.68 27.6 C-44 2 4-n-propyl-phenyl " 141-4 ethanol 95% 0.78 11.0 C-45 2 3,4-dimethyl-phenyl n-propyl-amino 155-7 isopropanol 0.76 20.2 C-46 2 3,4-dimethyl-phenyl n-hexyl-amino 156-8 acetonitrile 0.85 18.0 C-47 2 3,4-dimethyl-phenyl cyclohexyl-amino 210-2 methanol 0.73 62.8 C-48 2 4-ethyl-phenyl " 190-2 methanol 0.78 31.3 C-49 2 4-isopropyl-phenyl " 208-12 methanol/water 4:1 0.82 18.6 C-50 2 3,4-dimethyl-phenyl dimethyl-amino 152-4 water/ethanol 9:1 0.37 29.0 C-51 2 3,4-dimethyl-phenyl morpholine 147-50 ethanol 0.80 40.0 C-52 2 3,4-dimethyl-phenyl piperidine 172-4 methanol 0.82 33.8 C-53 2 3-methyl-phenyl di-n-butyl-amino 92-7 ethanol/water 1:1 0.88 12.7 C-54 2 3,4-dimethyl-phenyl " 105-8 acetonitrile 0.91 13.3 C-55 2 3,4-dimethyl-phenyl di-n-pentyl-amino 109-11 ethanol/water 1:1 0.92 40.5 __________________________________________________________________________ (*) Eluent used: isoamyl alcohol-acetone-H.sub.2 O (5.2.1)
TABLE D __________________________________________________________________________ Derivatives of formula: ##STR10## MELTING SOLVENT OF YIELD COMPOUNDS n R.sub.1 R.sub.2 POINT (°C.) CRYSTALLIZATION Rf* (%) __________________________________________________________________________ D-1 2 3,4-dichloro-phenyl di-methyl-amino 148-52 H.sub.2 O/Ethanol 3:7 0.38 30.1 D-2 2 3,4-dichloro-phenyl di-n-butyl-amino 106-8 H.sub.2 O/Ethanol 1:1 0.62 17.0 D-3 1 3,4-dichloro-phenyl n-butyl-amino 131-4 H.sub.2 O/Ethanol 1:1 0.36 43.3 D-4 2 4-bromo-phenyl di-butyl-amino 104-7 Isopropyl ether 0.50 19.9 D-5 2 3-cyano-phenyl di-butyl-amino 115-8 Ethyl acetate 0.50 28.2 D-6 2 4-bromo-phenyl morpholino 186-9 H.sub.2 O/Ethanol 3:7 0.35 69.5 D-7 2 4-bromo-phenyl piperidino 132-5 H.sub.2 O/Ethanol 3:7 0.35 40.8 D-8 2 4-cyano-phenyl di-butyl-amino 112-6 Ethyl acetate 0.51 21.3 D-9 2 3,4-dichloro-phenyl piperidino 101-3 H.sub.2 O/Ethanol 1:1 0.48 29.6 D-10 2 4-cyano-phenyl piperidino 177-9 H.sub.2 O/Ethanol 3:4 0.28 37.6 D-11 2 3-cyano-phenyl piperidino 106-10 Ethyl acetate 0.22 38.9 D-12 2 3,4-dimethyl phenyl di-methyl amino 204-6 methanol 0.27 57.6 D-13 2 4-ethyl phenyl n-butyl amino 137-9 methanol 0.48 37.5 D-14 2 4-propyl phenyl n-butyl amino 138-40 methanol 0.40 53.8 D-15 2 3,4-dimethyl phenyl di-n-propyl amino 118-21 methanol - H.sub.2 O 0.47) 28.8 D-16 2 3,4-dimethyl phenyl n-propyl amino 167-9 H.sub.2 Oacetonitrile 0.44) 41.5 D-17 2 4-isopropyl phenyl piperidine amino 152-4 isopropyl alcohol 0.34 40.3 __________________________________________________________________________ *Eluent used: isoamyl alcohol acetone H.sub.2 O (5.2.1).
TABLE 1 Activity of the listed compounds of the invention in potentiating the analgesia of opiates in the Tail Flick Test Times Treatment 10' 20' 30' 4 5' 60' 90' M (10-90) ± SE Power ratio with respect Controls -10.2 ± 9.3 19.6 ± 4.1 46.4 ± 8.2 -8.7 ± 13.5 18.2 ± 5.1 19.9 ± 8.3 14.2 ± 8.6 to morphine alone Morphine (M) 10.8 ± 4.0 54.2 ± 17.0 46.6 ± 21.0 41.7 ± 16.0 32.0 ± 17.0 -6.4 ± 10.0 29.8 ± 23.0 1 M + C-1 65.3 ± 18.0 67.2 ± 15.0 66.3 ± 14.0 82.7 ± 11.0 68.8 ± 17.0 59.3 ± 25.0 68.2 ± 8.0 2.29 M + C-2 27.8 ± 13.0 43.8 ± 25.0 67.5 ± 20.0 64.2 ± 22.0 74.4 ± 16.0 57.3 ± 19.0 55.8 ± 17.0 1.87 M + C-3 44.4 ± 23.3 83.7 ± 16.3 77.8 ± 17.1 46.4 ± 24.5 73.6 ± 17.7 45.8 ± 22.8 61.9 ± 18.2 2.10 M + C-4 44.6 ± 5.3 67.5 ± 13.4 66.3 ± 14.0 60.4 ± 16.3 59.8 ± 17.0 44.2 ± 14.8 57.1 ± 10.3 1.92 M + C-5 34.5 ± 17.4 21.4 ± 16.0 59.5 ± 21.1 84.7 ± 15.2 63.9 ± 18.5 40.1 ± 23.9 50.7 ± 23.0 1.70 M + C-6 89.2 ± 6.7 91.3 ± 8.7 83.6 ± 10.0 82.1 ± 16.6 79.8 ± 17.0 38.2 ± 10.6 77.4 ± 19.6 2.59 M + C-7 67.9 ± 14.3 71.5 ± 17.6 79.4 ± 10.0 84.6 ± 10.5 92.9 ± 4.1 72.6 ± 7.0 78.2 ± 9.4 2.62 M + C-8 67.4 ± 20.5 74.1 ± 15.8 80.0 ± 12.9 85.9 ± 14.1 87.1 ± 12.9 60.4 ± 17.3 75.8 ± 10.6 2.54 M + C-9 67.6 ± 11.0 65.8 ± 20.0 71.9 ± 17.5 59.1 ± 20.0 52.1 ± 22.0 40.4 ± 18.0 59.5 ± 11.6 2.00 M + C-10 56.9 ± 25.8 66.4 ± 21.4 72.9 ± 16.8 70.1 ± 18.5 66.2 ± 21.3 63.2 ± 23.4 66.0 ± 5.6 2.21 M + C-11 25.2 ± 4.0 37.6 ± 16.0 50.9 ± 11.0 54.4 ± 9.0 35.8 ± 5.0 18.7 ± 10.0 37.1 ± 14.0 1.24 M + C-12 54.4 ± 16.7 76.3 ± 19.0 61.6 ± 16.0 63.9 ± 20.0 65.2 ± 17.0 11.6 ± 14.0 55.5 ± 22.0 1.86 M + C-13 24.6 ± 8.9 70.0 ± 18.5 75.5 ± 15.0 56.6 ± 19.5 62.3 ± 17.3 59.2 ± 25.1 58.0 ± 18.0 1.95 M + C-14 36.5 ± 28.4 76.0 ± 12.7 79.3 ± 10.6 77.0 ± 6.7 98.3 ± 1.3 71.9 ± 13.2 73.1 ± 20.0 2.45 M + C-15 59.8 ± 14.0 84.2 ± 9.6 78.3 ± 13.5 88.7 ± 8.5 82.5 ± 12.7 54.5 ± 14.7 74.7 ± 14.0 2.51 M + C-16 43.2 ± 11.0 88.7 ± 10.0 54.8 ± 5.8 47.3 ± 11.8 26.1 ± 11.5 22.2 ± 16.7 47.0 ± 24.0 1.58 M + C-17 18.9 ± 10.0 37.0 ± 12.0 45.8 ± 18.0 41.0 ± 17.0 39.3 ± 20.0 31.2 ± 18.0 35.5 ± 9.5 1.19 M + C-18 48.9 ± 31.0 65.9 ± 24.0 80.1 ± 9.0 59.1 ± 20.0 33.5 ± 20.0 81.4 ± 12.0 58.1 ± 15.8 1.95 M + C-19 3.6 ± 12.0 42.8 ± 19.0 58.4 ± 21.0 66.1 ± 16.0 57.1 ± 18.0 35.6 ± 20.0 43.9 ± 22.7 1.47 M + C-20 53.8 ± 21.4 85.7 ± 10.0 92.0 ± 8.0 99.1 ± 1.0 91.2 ± 9.0 51.2 ± 14.0 78.8 ± 21.0 2.64 M + C-21 48.6 ± 19.0 37.4 ± 12.0 54.8 ± 19.0 44.6 ± 15.0 64.0 ± 18.0 54.9 ± 10.0 50.7 ± 9.0 1.70 M + C-22 82.7 ± 9.4 67.6 ± 18.0 88.4 ± 9.3 83.3 ± 10.5 93.6 ± 6.4 53.8 ± 14.9 78.2 ± 15.0 2.62 Morphene (M) 10.8 ±4 54.2 ±17 46.6 ± 21 41.7 ± 1632 ± 17 -6.4 ± 10 29.8 ± 23 1 M + C-28 15.7 ± 10 66.8 ± 18 68.3 ± 20 68.4 ± 17 74.5 ± 11 27.5 ± 15 53.5 ± 25 1.80 M + C-29 48.7 ± 20 75.5 ± 10.5 73.6 ± 11 70.0 ± 19 47.3 ± 23 6.0 ± 14 53.5 ± 26 1.80 M + C-30 69.9 ± 16 100.0 ± 0 95.2 ± 4.8 91.8 ± 8 100 ± 0 100.0 ± 0 92.8 ± 12 3.11 M + C-31 28.9 ± 17 43.3 ± 25 54.7 ± 22 68.0 ± 22 57.4 ± 16 49.5 ± 19 50.4 ± 14 1.69 M + C-32 21.8 ± 5 58.6 ± 17 83.5 ± 10 89.8 ± 8 78.4 ± 13 52.2 ± 22 64.0 ± 25 2.15 M + C-33 -0.1 ± 12 30.9 ± 8 38.7 ± 21 41.7 ± 16 48.7 ± 21 46.6 ± 12 34.4 ± 18 1.15 M + C-34 19.6 ± 23 59 ± 17 85.5 ± 10 78.4 ± 16 67 ± 20 59.1 ± 23 60.6 ± 23 2.03 M + C-35 39.9 ± 15 62.3 ± 23 13.7 ± 26 63.2 ± 17 61.3 ± 20 28.8 ± 31 44.9 ± 21 1.51 M + C-36 8.6 ± 13 100.0 ± 0 96.9 ± 3 90.0 ± 10 96.9 ± 3 92.4 ± 25 80.8 ± 36 2.71 M + C-37 27.6 ± 13 45.8 ± 18 55.0 ± 16 51.1 ± 18 23.4 ± 21 12.4 ± 13 35.9 ± 17 1.20 M + C-38 53.8 ± 21 85.7 ± 10 92.0 ± 8 99.1 ± 1 91.2 ± 9 51.1 ± 14 78.8 ± 21 2.64 M + C-39 44.9 ± 15 100.0 ± 0 93.3 ± 7 94.4 ± 6 85.6 ± 7 81.8 ± 10 83.3 ± 20 2.79 M + C-40 43.8 ± 15 69.1 ± 14 49.0 ± 23 85.6 ± 6 76.5 ± 17 61.5 ± 14 64.2 ± 16 2.15 M + C-41 32.1 ± 18 60.0 ± 22 40.0 ± 17 46.7 ± 23 11.5 ± 14 7.4 ± 20 32.9 ± 20 1.10 M + C-42 49.0 ± 31 65.9 ± 24 80.1 ± 9 59.1 ± 20 33.5 ± 20 61.4 ± 12 58.2 ± 16 1.95 M + C-43 54.1 ± 17 44.4 ± 23 38.9 ± 26 36.8 ± 27 47.8 ± 23 22.5 ± 13 40.7 ± 11 1.36 M + C-44 -1.6 ± 11 17.0 ± 6 24.9 ± 10 26.9 ± 19 35.1 ± 17 39.8 ± 8 23.7 ± 15 0.79 M + C-45 57.2 ± 18 99.7 ± 0.3 95.7 ± 4 93.1 ± 7 77.7 ± 11 80.4 ± 9 84.0 ± 16 2.82 M + C-46 14.7 ± 9 60.0 ± 18 28.0 ± 5 55.2 ± 20 30.2 ± 17 12.2 ± 11 32.9 ± 21 1.10 M + C-47 24.5 ± 14 63.5 ± 18 52.3 ± 17 80.1 ± 22 73.2 ± 17 49.3 ± 19 57.1 ± 20 1.92 M + C-48 42.1 ± 14 59.5 ± 8 50.1 ± 21 78.4 ± 18 43.7 ± 30 44.9 ± 18 53.1 ± 14 1.78 M + C-49 62.1 ± 9 100.0 ± 0 97.6 ± 2 99.5 ± 0.5 99.2 ± 0.5 65.8 ± 0.8 87.4 ± 18 2.93 M + C-50 22.3 ± 13 68.9 ± 9 60.2 ± 19 49.4 ± 14 73.5 ± 15 24.7 ± 6 49.8 ± 22 1.67 M + C-51 78.7 ± 18 82.8 ± 12 90.5 ± 10 86.4 ± 14 65.6 ± 13 48.5 ± 10 75.4 ± 16 2.53 M + C-52 72.8 ± 15 95.8 ± 3 96.3 ± 4 85.5 ± 10 87.6 ± 8 45.3 ± 6 80.6 ± 19 2.70 M + C-53 31.2 ± 15 46.7 ± 28 70.2 ± 23 76.9 ± 22 45.6 ± 27 12.6 ± 25 47.2 ± 24 1.58 M + C-54 77.0 ± 10 89.1 ± 11 100 ± 0 99.2 ± 0.8 69.6 ± 16 63.2 ± 19 83.0 ± 15 2.78 M + C-55 89.3 ± 16 86.2 ± 12 94.4 ± 5 100 ± 0 100 ± 0 81.7 ± 13 88.6 ± 12 2.97 M + C-23 33.1 ± 19.0 49.9 ± 15.0 58.2 ± 17.0 68.3 ± 20.0 72.0 ± 18.0 58.7 ± 22.0 56.7 ± 14.0 1.90 M + C-24 80.3 ± 13.6 87.2 ± 13.0 96.9 ± 3.0 100.0 ± 0.0 74.0 ± 16.0 75.3 ± 14.0 85.6 ± 11.0 2.87 M + C-25 59.7 ± 15.0 49.0 ± 13.0 71.5 ± 13.0 61.9 ± 22.0 49.0 ± 22.0 20.4 ± 6.0 51.9 ± 18.0 1.74 M + C-26 50.1 ± 17.0 80.3 ± 20.0 84.7 ± 11.0 71.8 ± 15.0 32.2 ± 7.0 4.9 ± 6.0 54.0 ± 31.1 1.81 M + C-27 52.3 ± 13.0 81.4 ± 12.0 90.2 ± 7.0 85.9 ± 10.0 60.3 ± 15.0 50.3 ± 13.0 70.0 ± 17.8 2.35 N + D-1 75.0 ± 16.0 100.0 ± 0.0 100.0 ± 0.0 86.4 ± 14.0 100.0 ± 0.0 51.0 ± 21.0 85.4 ± 19.7 2.86 M + D-2 85.6 ± 14.0 98.1 ± 2.0 95.9 ± 4.0 96.6 ± 3.0 95.5 ± 3.0 87.5 ± 6.0 93.2 ± 5.3 3.12 M + D-3 63.8 ± 17.0 79.9 ± 13.0 100.0 ± 0.0 58.6 ± 18.0 33.8 ± 18.0 32.9 ± 10.0 61.5 ± 26.2 2.06 M + D-4 72.8 ± 15.0 95.8 ± 3.0 96.3 ± 4.0 85.5 ± 10.0 87.5 ± 8.0 45.3 ± 6.0 80.5 ± 19.3 2.70 M + D-5 72.2 ± 17.0 92.5 ± 7.0 95.3 ± 5.0 96.0 ± 4.0 74.3 ± 11.0 75.5 ± 11.0 84.3 ± 11.4 2.83 M + D-6 31.2 ± 22.0 45.8 ± 23.0 50.7 ± 20.0 44.5 ± 24.0 45.3 ± 24.0 28.2 ± 19.0 41.0 ± 9.0 1.37 M + D-7 31.8 ± 19.0 48.0 ± 16.0 70.5 ± 15.0 73.7 ± 13.0 88.6 ± 11.0 32.4 ± 19.0 57.5 ± 23.5 1.93 M + D-8 29.0 ± 15.0 50.9 ± 8.0 61.4 ± 22.0 57.7 ± 18.0 52.9 ± 20.0 28.3 ± 12.0 46.7 ± 14.4 1.56 M + D-9 88.5 ± 19.0 74.0 ± 16.0 70.9 ± 16.0 73.0 ± 15.0 84.5 ± 12.0 79.9 ± 12.0 75.1 ± 6.0 2.52 M + D-10 41.0 ± 8.0 58.6 ± 17.0 59.8 ± 17.0 62.7 ± 15.0 47.0 ± 15.0 35.4 ± 11.0 50.8 ± 11.2 1.70 M + D-11 25.3 ± 7.0 68.3 ± 20.0 74.8 ± 18.0 82.8 ± 17.0 86.2 ± 14.0 77.5 ± 13.0 69.1 ± 22.3 2.32 M + D-12 45.4 ± 23 63.9 ± 15 84. ± 16 100 ± 0 78.5 ± 15 56.1 ± 22 71.3 ± 20 2.39 M + D-13 7.1 ± 8 32 ± 19 62.5 ± 23 31.8 ± 21 48.5 ± 22 50.9 ± 14 38.8 ± 20 1.30 M + D-14 69.2 ± 14 93.4 ± 7 46.8 ± 15 71.3 ± 17 89.1 ± 9 60.3 ± 71.1 ± 14 2.41 M + D-15 43.5 ± 16 48.7 ± 18 72.6 ± 19 60.1 ± 23 59.2 ± 18 43.5 ± 24 54.6 ± 11 1.83 M + D-16 29.7 ± 21 42.8 ± 18 40.1 ± 22 35.4 ± 18 33.3 ± 20 23.3 ± 20 34.1 ± 17 1.14 M + D-17 62.3 ± 15 92.9 ± 7 100 ± 0 100 ± 0 100 ± 0 100 ± 0 92.5 ± 15 3.10
TABLE 2a __________________________________________________________________________ Power of several compounds which are the subject of the invention to potentiate the activity of analgesic drugs in the hot-plate test. TOTAL posi- DOSAGE tives TREATMENT mg/kg i.p. 10' 20' 30' 45' 60' 90' x/30 __________________________________________________________________________ Propoxyphene (Pr.) 15 2/5 2/5 3/5 3/5 1/5 3/5 12 Pr + Compound C-20 15 + 1 (C-20) 2/5 2/5 3/5 3/5 3/5 3/5 16 Pr + Compound C-20 15 + 3 (C-20) 3/5 5/5 4/5 5/5 4/5 4/5 25 Pr + Compound C-20 15 + 10 (C-20) 4/5 5/5 5/5 5/5 5/5 3/5 27 Oxyphenylbutazone (Oxy) 50 2/5 1/5 2/5 2/5 0/5 0/5 7 Oxy + Compound D-2 50 + 3 (D-2) 2/5 1/5 2/5 3/5 3/5 1/5 12 Oxy + Compound D-2 50 + 10 (D-2) 1/5 1/5 3/5 3/5 2/5 2/5 12 Oxy + Compound D-2 50 + 30 (D-2) 3/5 4/5 4/5 4/5 4/5 4/5 23 Acetyl Salicylic Acid (ASA) 100 1/5 2/5 2/5 2/5 0/5 1/5 8 Asa + Compound C-20 100 + 5 (C-20) 2/5 2/5 2/5 3/5 3/5 0/5 12 Asa + Compound C-20 100 + 20 (C-20) 1/5 3/5 3/5 3/5 4/5 3/5 17 Asa + Compound C-20 100 + 50 (C-20) 3/5 2/5 5/5 5/5 4/5 3/5 22 __________________________________________________________________________
TABLE 2b __________________________________________________________________________ Total posi- Dosage tives TREATMENT mg/kg i.p. 10' 20' 30' 45' 60' 90' X/30 __________________________________________________________________________ Propoxyphene (Prop.) 10 1/5 2/5 2/5 2/5 1/5 0/5 8 Prop. + Compound C-30 10 + 0.3 (C-30) 2/5 1/5 3/5 3/5 2/5 0/5 11 Prop. + Compound C-30 10 + 1 (C-30) 3/5 4/5 4/5 4/5 2/5 2/5 19 Prop. + Compound C-30 10 + 3 (C-30) 3/5 5/5 5/5 5/5 4/5 3/5 25 Methadone (Met.) 1 1/5 2/5 1/5 2/5 1/5 1/5 8 Met. + Compound C-36 1 + 0.3 (C-36) 2/5 2/5 3/5 3/5 1/5 1/5 2 Met. + Compound C-36 1 + 1 (C-36) 3/5 5/5 4/5 3/5 3/5 1/5 19 Met. + Compound C-36 1 + 3 (C-36) 5/5 5/5 3/5 4/5 5/5 2/5 24 Oxyphenylbutazone (oxy) 50 2/5 1/5 2/5 2/5 0/5 0/5 7 Oxy + Compound C-30 50 + 3 (C-30) 1/5 1/5 3/5 2/5 2/5 2/5 11 Oxy + Compound C-30 50 + 10 (C-30) 1/5 2/5 2/5 3/5 3/5 2/5 12 Oxy + Compound C-30 50 + 30 (C-30) 2/5 3/5 4/5 4/5 4/5 3/5 20 Acetyl Salicylic Acid (Asa) Asa + Compound C-36 100 1/5 2/5 2/5 2/5 0/5 1/5 8 Asa + Compound C-36 100 + 10 (C-36) 1/5 2/5 3/5 2/5 1/5 1/5 10 Asa + Compound C-36 100 + 30 (C-36) 1/5 2/5 2/5 3/5 3/5 3/5 14 Asa + Compound C-36 100 + 100 (C-36) 3/5 3/5 4/5 4/5 4/5 2/5 20 __________________________________________________________________________
TABLE 3 __________________________________________________________________________ Average latency (in sec) determined by the Tail Flick Test at different times (minutes) from the electric shock (average values for groups of 5 animals ± ES). Dose Time TREATMENT mg/kg iv 5' 10' 15' __________________________________________________________________________ A: Controls -- -2.88 ± 0.11 3.04 ± 0.29 2.70 ± 0.27 B: Controls stressed -- 5.16 ± 0.23 3.98 ± 0.203 3.10 ± 0.19 tv. A 8.74*** 2.54* 1.073 C: Compound C-20 + 1 7.5 ± 0.3 5.34 ± 0.46 3.88 ± 0.29 stress tv. A 11.18*** 4.21** 2.79* tv. B 6.03*** 2.67 2.20 D: Compound C-20 + 3 8.48 ± 0.62 6.42 ± 0.21 4.98 ± 0.36 stress tv. A 8.81*** 9.23*** 4.92** tv. B 4.97** 8.77*** 4.0** E: Compound D-2 + 1 9.2 ± 0.53 7.0 ± 0.86 5.28 ± 0.64 stress tv. A 10.50*** 4.42** 3.59** 6.94*** 3.49** 3.22* F: Compound D-2 + 3 9.6 ± 0.46 7.24 ± 0.58 5.08 ± 0.52 stress tv. A 12.42*** 6.38*** 3.97** tv. B 8.47** 5.29** 3.57** Note: *P < 0.05 **P < 0.01 ***P < 0.001
G: Compound C-30 + 1 7.26 ± 0.52 6.10 ± 0.49 4.68 ± 0.5 stress tv. A 8.11*** 5.34** 3.10** tv. B 3.64** 3.97** 2.67* H: Compound C-30 + 3 9.46 ± 0.64 7.96 ± 0.61 6.82 ± 0.78 stress tv. A 10.06*** 7.22*** 4.95** tv. B 6.28*** 6.14*** 4.65** I: Compound C-34 + 1 5.40 ± 0.35 4.9 ± 0.25 3.4 ± 0.16 stress tv. A 7.05*** 4.80** 2.24 tv. B 0.76 2.82* 1.44 L: Compound C-34 + 3 6.56 ± 0.33 5.58 ± 0.31 3.98 ± 0.32 stress tv. A 7.11*** 5.92*** 2.92* tv. B 3.45** 4.26** 2.36* M: Compound C-36 + 1 6.9 ± 0.74 6.5 ± 0.42 4.66 ± 0.55 stress tv. A 5.34*** 6.72*** 2.92* tv. B 3.31** 5.36*** 2.48* N: Compound C-36 + 3 9.22 ± 0.67 8.1 ± 0.43 9.28 ± 0.64 stress tv. A 7.70*** 9.84*** 9.30*** tv. B 5.66*** 8.74*** 9.18*** O: Compound C-39 + 1 6.3 ± 0.4 5.8 ± 0.38 4.04 ± 0.36 stress tv. A 8.21*** 5.72*** 2.85* tv. B 2.46 4.18* 2.30 P: Compound C-39 + 3 7.54 ± 0.65 5.98 ± 0.41 5.08 ± 0.6 stress tv. A 5.05*** 5.55*** 3.51** tv. B 4.43** 4.43** 3.12* Q: Compound D-17 + 1 6.18 ± 0.65 7.02 ± 0.76 5.31 ± 0.55 stress tv. A 4.97** 4.90** 4.16** tv. B 1.47 3.89** 3.79** R: Compound D-17 + 3 9.08 ± 0.55 9.08 ± 0.80 6.08 ± 0.98 stress tv. A 10.96*** 7.02*** 3.28* tv. B 6.52*** 6.14*** 2.99* __________________________________________________________________________ Note: *P > 0.05 **P > 0.01 ***P > 0.001
TABLE 4 __________________________________________________________________________ Increase in the analgesic activity of DALA induced by several compounds of the invention determined by the Tail Flick Test in rats. Times GROUP TREATMENT Doses 10' 20' 30' 45' 60' 90' MEAN Student's __________________________________________________________________________ μg/kg(ICV) A Controls -- -3.3 ± 0.3 ± 0.9 ± -4.3 ± -3.0 ± -1.1 ± -2.0 ---. 4.6 5.2 4.5 5.0 5.5 5.0 2.1 B DALA (D) 10 21.9 ± 25.9 ± 26.2 ± 26.0 ± 7.3 ± 5.0 ± 18.7 v. A: 20.0 19.2 18.8 19.2 7.1 5.7 9.9 5.07*** C DALA + 10(D) + 0.003 5.7 ± 44.6 ± 32.3 ± 30.1 ± 24.5 ± 72. ± 24.1 v. A: Compound 4.4 15.6 14 9.3 7.7 3.6 13.8 4.20** C-20 v. B: 0.72 D DALA + 10(D) + 0.01 16.5 ± 62.5 ± 64.1 ± 45.4 ± 45.3 ± 16.3 ± 41.7 v. A: Compound 4.7 18.7 22.2 18.4 20.8 5.8 21.2 5.0*** C-20 v. B: 2.41* E DALA + 10(D) + 0.003 34.9 ± 54.0 ± 45.5 ± 27.5 ± 23.5 ± 14.9 ± 33.4 V. A: Compound 24.1 26.7 21.6 15.4 9.2 8.1 14.5 5.95*** D-2 v. B: 2.05 F DALA + 10(D) + 0.01 38.2 ± 53.7 ± 52.6 ± 38.5 ± 33.7 ± 26.3 ± 40.5 V. A: Compound 18.3 19.8 16.0 16.4 16.9 13.0 9.8 9.59*** D-2 v. B: 3.66** mg/kg(ICV) AA Controls -- 0.68 ± 5.64 ± 1.43 ± 4.86 ± 4.21 ± 4.91 ± 3.62 ---. 5.45 4.83 4.42 3.90 4.41 2.25 2.05 BB DALA (D) 10 4.1 ± 6.24 ± 9.19 ± 8.29 ± 6.20 ± 10.56 ± 7.51 v. A: 8.89 4.0 2.92 1.69 2.60 3.87 2.31 3.08* G DALA + 10(D) + 0.01 58 ± 60.8 ± 77.0 ± 66.4 ± 48.8 ± 45.0 ± 59.33 v. A: Compound 15.3 14.2 16.7 12.4 16.2 11.1 11.7 11.5*** C-30 v. B: 10.6*** H DALA + 10(D) + 0.01 59.1 ± 67.8 ± 86.0 ± 83.3 ± 83.3 ± 55.1 ± 73.26 v. A: Compound 15.2 16.0 9.5 8.4 6.41 16.2 14.5 11.6*** C-30 v. B: 11.0*** I DALA + 10(D) + 0.03 41.1 ± 55.6 ± 38.5 ± 35.88 ± 32.63 ± 25.44 ± 38.19 v. A: Compound 14.7 15.0 19.61 14.31 15.89 16.59 10.1 8.2*** D-36 v. B: 7.25*** L DALA + 10(D) + 0.03 55.82 ± 70.58 ± 53.13 ± 35.17 ± 38.00 ± 20.62 ± 45.55 v. A: Compound 1.89 18.43 17.63 15.95 13.60 9.35 17.7 5.75*** D-36 v. B: 5.2*** __________________________________________________________________________ Note: *P < 0.05 **P < 0.01 ***P < 0.001
TABLE 5 __________________________________________________________________________ Antagonism of several products of the invention to the development of tolerance induced in rats by the repeated administration of morphine __________________________________________________________________________ HCl Dose Time Time Time Time Time Time Time Time TREATMENT mg/kg ip 0 24 h 48 h 72 h 96 h 120 h 144 h 168 __________________________________________________________________________ h A: Controls -- -0.73 ± 0.86 ± 5.43 ± 1.09 + 3.97 ± 1.47 + 1.08 ± -0.77 ± 4.10 1.04 1.18 1.90 1.00 1.58 3.12 1.08 Effect % = -0.0040 · h + 1.89 (r = 0.11; t = 0.27 NS) B: Morphine 5 mg/kg + 58.03 ± 42.09 ± 26.54 ± 19.96 + 10.79 ± 4.45 ± 3.58 ± 2.12 ± (M) 11.20 19.20 15.90 7.03 7.05 0.69 3.31 3.47 Effect % = -0.327 · h + 48.42 (r = 0.95; t = 7.22***) C: Compound 10 mg/kg + 47.32 43.65 32.80 31.78 35.45 42.08 29.33 19.17 D-8 (M) Effect % = -0.118 · h + 45.08 (r = 0.76; t = 2.89*) D: Compound 10 mg/kg + 72.15 53.36 48.17 53.67 31.56 41.67 14.48 13.75 C-20 (M) Effect % = -0.320 · h + 67.97 (r = 0.93; t = 6.12***) E: Compound 10 mg/kg + 74.14 45.73 59.50 51.52 43.40 37.60 21.43 29.75 D-2 (M) Effect % = -0.251 · h + 66.47 (r = 0.89; t = 4.65**) __________________________________________________________________________ Dose Time Time Time Time Time Time Time Time TREATMENT mg/kg ip 0 +24 h +48 h + 72 h +96 h +120 h +144 h 168 __________________________________________________________________________ h A: Controls -- -0.73 ± 0.86 ± 5.43 ± 1.09 ± 3.97 ± 1.47 ± 1.08 ± -0.77 ± 4.1 1.04 1.18 1.90 1.0 1.58 3.12 1.08 B: Morphine 5 mg/g + 58.03 ± 42.09 ± 26.54 ± 19.96 ± 10.79 ± 4.45 ± 3.58 ± 2.12 ± (M) 11.2 19.2 15.9 7.03 7.05 0.69 3.31 3.47 Student's t -- 9.86*** 4.29** 2.64* 5.18** 1.91 3.45* 1.1 1.58 v. A F: Compound 10 mg/kg + 74.51 ± 66.53 ± 50.61 ± 47.53 ± 29.65 ± 34.24 ± 26.97 ± 71.81 ± C-30 + (M) 9.7 15.1 15.5 15.7 12.1 9.11 10.04 24.0 morphine Student's t -- 14.32*** 8.67*** 5.82** 5.86** 4.23** 5.18** 4.92** 9.43*** v. A Student's t -- 2.23 2.00 2.16 3.2* 2.69* 4.79** 4.42** 6.96*** v. B G: Compound 10 mg/g + 44.52 ± 67.27 ± 67.31 ± 56.04 ± 49.48 ± 34.34 ± 27.50 ± 17.47 ± C-30 + (M) 17.2 9.6 14.0 8.55 2.26 10.34 6.13 8.07 Morphine Student's t -- 5.11** 13.78*** 8.83*** 12.54*** 36.76*** 6.18*** 7.91*** 4.47** v. A Student's t -- 1.31 2.35 3.84** 6.51*** 10.45*** 5.76** 6.86*** 3.49** v. B __________________________________________________________________________ Note: *(P < 0.05) **(P < 0.01) ***(P < 0.001) Calculated straight lines of regression: Group B: = Activity = -0.327 × hour + 48.41 (coeffic. of correlatio = 0.95) Group C: = Activity = -0.118 × hour + 45.08 (coeffic. of correlatio = 0.76) Group D: = Activity = -0.320 × hour + 67.97 (coeffic. of correlatio = 0.93) Group E: = Activity = -0.251 × hour + 66.47 (coeffic. of correlatio = 0.89) Group F: = Activity = -0.314 × hour + 70.38 (r = 0.96) Group G: = Activity = -0.245 × hour + 66.06 (r = 0.79)
TABLE 6 ______________________________________ In vitro anti-CCK-8 activity of the compounds of the invention (concentration used - 10 ng/ml) on guinea pig gall bladders, expressed as the ED 50 in μg/ml. ACTIVITY ED50 ACTIVITY COMPOUNDS (μg/ml) COMPOUNDS ED50 (μg/ml) ______________________________________ Compound C-1 >200 Compound C-20 >200 Compound C-2 >200 Compound C-21 >200 Compound C-3 34.4 Compound C-22 >200 Compound C-4 1.1 Compound C-23 >200 Compound C-5 4.2 Compound C-24 >200 Compound C-6 0.33 Compound C-25 30.3 Compound C-7 0.06 Compound C-26 146.5 Compound C-8 0.93 Compound C-27 10.2 Compound C-9 7.40 Compound D-1 >200 Compound C-10 43.7 Compound D-2 >200 Compound C-11 0.85 Compound D-3 >200 Compound C-12 64.7 Compound D-4 >200 Compound C-13 >200 Compound D-5 >200 Compound C-14 118.4 Compound D-6 >200 Compound C-15 >200 Compound D-7 >200 Compound C-16 >200 Compound D-8 >200 Compound C-17 >200 Compound D-9 >200 Compound C-18 60.3 Compound D-10 >200 Compound C-19 >200 Compound D-11 >200 Compound C-28 >300 Compound C-36 13.4 Compound C-29 262 Compound C-42 50.1 Compound C-30 33.5 Compound C-47 35.1 Compound C-31 22.9 Compound C-48 119.1 Compound C-32 >300 Compound D-12 >300 Compound C-33 131.7 Compound D-15 245.0 Compound C-34 40.1 Compound D-17 >300 Compound C-35 367.1 Compound C-54 1.2 Compound C-55 0.5 ______________________________________
TABLE 7 __________________________________________________________________________ Anti-CCK-8 activity of several of the compounds of the invention (concentration used - 10 ng/kg) on guinea pig gall bladders in situ expressed as the ED50 in mg/kg i.v. ED50 (mg/kg i.v.) DOSE EXPERIMENT EXPERIMENT EXPERIMENT EXPERIMENT r: (coeff. of COMPOUNDS (mg/kg i.v.) 1 2 3 4 correlation) __________________________________________________________________________ C-4 0.03 -- -- -11.8 0.30 0.10 -36.7 -49.3 -40.0 (r: 0.90) 0.30 -44.6 -68.4 -51.7 t = 5.46*** 1.00 -92.1 -88.5 -- C-6 0.01 -- -- -12.9 0.05 0.03 -- -49.7 -40.0 (r: 0.96) 0.10 -72.6 -55.8 -62.9 t = 9.07*** 0.30 -97.0 -82.8 -- 1.00 -100.0 -- -- C-7 0.003 -- -- -10.6 0.02 0.01 -36.8 -28.2 -25.9 (r: 0.98) 0.03 -62.1 -57.0 -59.2 t = 13.9*** 0.10 -77.5 - 89.8 -94.7 Compound C-30 3 16.7 0 6.0 -- 13.8 10 14.6 20.8 31.1 -- Coefficient of 30 82.1 92.5 79.5 correlation (r): 0.91 Compound C-31 3 16.7 0 22.8 -- 16.3 10 14.6 0 31.7 -- (r): 0.80 30 82.1 92.5 58.7 -- Compound C-36 1 4.3 15.7 32.7 -- 5.1 3 30.0 12.1 40.0 20.3 (r): 0.91 10 64.8 71.6 63.3 78.7 30 -- -- -- 100 __________________________________________________________________________ ***P < 0.001
TABLE 8 ______________________________________ Examples of anti-spastic activity for the compounds claimed administered intraperitoneally in mice. Values expressed as the ED 50 in mg/kg, that is the dose which reduces the intestinal transit of carbon by 50% ANTISPASTIC ACTIVITY: COMPOUND ED50 mg/kg (i.p.) ______________________________________ Compound C-28 91.8 Compound C-30 77.7 Compound C-34 65.5 Compound C-35 180.9 Compound C-36 208 Compound C-37 160.1 Compound C-41 182.4 Compound C-46 66.9 Compound C-4 38.8 Compound C-6 29.5 Compound C-7 16.8 Compound C-20 77.5 Compound C-27 40.3 Compound D-2 50.7 Compound D-5 74.9 ______________________________________
TABLE 9 __________________________________________________________________________ Anit-spastic activity in the colon of rabbits stimulated by CCK-8. ED50 (mg/kg iv) DOSES EXPERIMENT EXPERIMENT EXPERIMENT r: (coeff. of COMPOUNDS (mg/kg iv) 1 2 3 correlation __________________________________________________________________________ C-6 0.1 0 -- -- ED50 = 1.53 0.3 -24.1 -14.9 -8.5 r = 0 943 1 -57.9 -45.0 -41.8 t = 8.05(***) 3 -91.7 -77.5 -81.6 C-7 0.1 0 -- -10.7 ED50 = 1.11 0.3 -19.1 -36.8 -21.8 r = 0.919 1 -42.6 -74.2 -64.5 t = 6.58(***) 3 -100.0 -100.0 -- __________________________________________________________________________ (***)P < 0,001)
TABLE 10 ______________________________________ Percentage variation in the biliary flow in rats induced by several compounds of the invention. EFFECT DOSES (% increase ED50 (mg/kg i.v.) (mg/kg with respect to r = (coeff. of COMPOUNDS i.v.) controls) correlation) ______________________________________ Compound C-6 3 +40.4 4.2 10 +69.8 (r = 0.93) 30 +88.7 Compound C-20 12.5 +48.5 19.4 25.0 +63.9 (r = 0.98) 50.0 +108.0 Compound D-11 12.5 +33.7 18.5 25.0 +80.0 (r = 0.98) 50.0 +118.8 Compound C-30 12.5 +33.7 18.5 25 +60.2 (r = 0.99) 50 +121.2 100 +197.8 Compound C-35 12.5 +9.6 29.5 25.0 +51.9 (r = 0.98) 50.0 +91.9 100 +159.7 Compound C-36 12.5 +15.5 26.75 25.0 +48.5 (r = 0.99) 100.0 +215.8 ______________________________________
TABLE 11 __________________________________________________________________________ Determination of the body weight (in g) of various groups measured at different times DOSE GROUPS (mg/kg os) TIME 0 WEEK 1 WEEK 2 WEEK 3 WEEK 4 __________________________________________________________________________ A: Control -- 166.1 ± 4.5 197.4 ± 3.8 238.6 ± 4.09 280.0 ± 3.94 B: Compound C-7 0.3 162.1 ± 2.48 201.3 ± 2.7 254.5 ± 2.66 315.2 ± 2.72 Student's t vsA 0.78 0.83 3.26** 7.33*** C: Compound C-7 1 166.0 ± 1.56 214.7 ± 1.93 267.5 ± 2.6 319.8 ± 2.49 Student's t vsA 0.021 4.06** 5.96*** 8.53*** D: Compound C-7 3 166.6 ± 1.73 227.9 ± 1.65 290.9 ± 2.6 349.5 ± 2.82 Student's t vsA 0.1 7.11*** 11.3*** 14.32*** Control -- 254.2 ± 7.71 278.9 ± 7.02 308.8 ± 4.7 352.6 ± 2.09 383.1 ± 2 Compound C-30 3 270.8 ± 8.3 310.2 ± 7.01 380.5 ± 6.5 409.7 ± 2.99 437.3 ± 55 Student's t t = 1.464 t = 3.14** t = 8.992*** t = 15.66*** t = 9.24*** Compound C-30 10 271.4 ± 9.3 332.9 ± 5.7 383.2 ± 6.5 439.1 ± 4.3 470.5 ± 6.5 Student's t VsA t = 1.427 t = 5.981*** t = 9.19*** t = 18.234*** t = 12.798*** Compound C-30 30 267.9 ± 7.7 315.7 ± 7.4 371.9 ± 7.9 437.1 ± 5.2 488.1 ± 6.4 Student's t VsA t = 1.252 t = 3.606** t = 6.82*** t = 15.108*** t = 15.668 __________________________________________________________________________ Note: **(P < 0.01) ***(P < 0.001)
TABLE 12 __________________________________________________________________________ Food consumption (in g/week) in the various groups treated determined at different times. DOSE GROUPS (mg/kg os) WEEK 1 WEEK 2 WEEK 3 WEEK 4 __________________________________________________________________________ A: Control -- 166.1 ± 1.87 197.6 ± 1.96 208.7 ± 2.16 B: Compound C-7 0.3 176.4 ± 3.70 216.8 ± 4.71 239.3 ± 4.07 Student's t vsA 2.5* 3.75** 6.72*** C: Compound C-7 1 199.6 ± 3.88 230.5 ± 3.09 261.4 ± 4.24 Student's t vsA 7.78*** 8.99*** 11.2*** D: Compound C-7 3 198.4 ± 3.66 244.8 ± 3.09 268.8 ± 4.86 Student's t vsA 7.87*** 12.87*** 12.68*** Control -- 174.3 ± 5.07 209.6 ± 5.01 175.4 ± 4.34 180.3 ± 3.78 Compound C-30 3 193.7 ± 3.58 233.2 ± 4.56 187.1 ± 8.40 204.0 ± 3.63 Student's t vsA t = 3.128** t = 3.482** t = 1.237N.S t = 4.527*** Compound C-30 10 219.8 ± 5.62 264.3 ± 5.61 234.5 ± 5.05 234.6 ± 3.99 Student's t vsA t = 6.012*** t = 7.273*** t = 8.875*** t = 9.884*** Compound C-30 30 233.7 ± 5.45 267.9 ± 4.92 247.0 ± 5.19 244.5 ± 4.06 Student's t vsA t = 7.982*** t = 8.307*** t = 10.582*** t = 11.655*** __________________________________________________________________________ Note: *(P < 0.05) **(P < 0.01) ***(P < 0.001) N.S. (not significant)
TABLE 13 __________________________________________________________________________ Inhibiting action of Compound C-7 on the growth of normal and tumoral pancreatic cells, induced by CCK-8 __________________________________________________________________________ PANCREATIC No. of Pancreas weight student's DNA student's TREATMENT Animals DOSE (mg) t (mg) t __________________________________________________________________________ A: CONTROL 10 -- 380 ± 29.7 -- 0.8 ± 0.10 -- B: CCK-8 .sup. 8.sup.(°) 10 mcg/kg (3 times 600 ± 54.1 3.76(**) 1.5 ± 0.11 4.72(***) per day) C: COMPOUND C-7 10 5 mg/kg (3 times 336 ± 22.6 1.18 0.93 ± 0.09 1.03 per day) D: COMPOUND 10 10 mcg/kg CCK-8 374 ± 25.4 vsA: 0.15 1.0 ± 0.08 vsA: 1.53 C-7 + CCK-8 + 5 mg/kg C-7 vsB: vsB: 4.05(***) 3.61(**) __________________________________________________________________________ Weight of No. of Pancreatic student's TUMORAL DNA student's TREATMENT Animals DOSE Carcinoma (mg) t (mg) t __________________________________________________________________________ A: CONTROL 10 -- 113 ± 7.66 -- 0.4 ± 0.05 -- B: CCK-8 .sup. 8.sup.(°) 10 mcg/kg (3 times 180 ± 15.2 4.17(***) 0.7 ± 0.13 2.79(*) per day) C: COMPOUND C-7 10 5 mg/kg (3 times 104 ± 7.5 0.86 0.42 ± 0.02 0.34 per day) D: COMPOUND 10 10 mcg/kg CCK-8 + 109.5 ± 6.2 vsA: 0.37 0.4 ± 0.02 vsA: 0 C-7 + CCK-8 5 mg/kg C-7 vsB: vsB: 4.64(***) 2.51(*) __________________________________________________________________________ .sup.(°) 2 animals died during the treatment (*)P < 0.05 (**)P < 0.01 (***)P < 0.001
Claims (6)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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IT67644A/84 | 1984-06-25 | ||
IT67644/84A IT1178982B (en) | 1984-06-25 | 1984-06-25 | GLUDAMIC ACID DERIVATIVES HAVING ANTAGONIST ACTIVITIES ON BIOACTIVE POLIPEP TIDES AND PROCEDURE FOR THEIR PREPARATION |
IT68070/84A IT1196751B (en) | 1984-10-26 | 1984-10-26 | New N-acyl glutamic or aspartic acid amide derivs. |
IT68070A/84 | 1984-10-26 |
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US4791215A true US4791215A (en) | 1988-12-13 |
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US06/746,065 Expired - Lifetime US4791215A (en) | 1984-06-25 | 1985-06-18 | Derivatives of glutamic acid and aspartic acid |
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AT (1) | AT390949B (en) |
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CA (1) | CA1325633C (en) |
CH (1) | CH674203A5 (en) |
DE (1) | DE3522506A1 (en) |
DK (1) | DK285685A (en) |
ES (1) | ES8604859A1 (en) |
FR (1) | FR2566397B1 (en) |
GB (1) | GB2160869B (en) |
IE (1) | IE57892B1 (en) |
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Cited By (14)
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EP0411668A2 (en) * | 1989-08-04 | 1991-02-06 | MERCK SHARP & DOHME LTD. | Central cholecystokinin antagonists for treatment of psychiatric disorders |
US5153191A (en) * | 1991-08-20 | 1992-10-06 | Warner-Lambert Company | Cholecystokinin antagonists useful for treating depression |
US5217957A (en) * | 1991-08-20 | 1993-06-08 | Warner-Lambert Company | Cholecystokinin antagonists useful for treating depression |
WO1993012791A1 (en) * | 1991-12-20 | 1993-07-08 | Merck Sharp & Dohme Limited | Central cholecystokinin antagonists having pharmaceutical activity |
US5399748A (en) * | 1990-07-12 | 1995-03-21 | James Black Foundation Limited | Derivatives of aspartic acid and glutamic acid having anticholecystokinin activity |
US5500430A (en) * | 1990-12-11 | 1996-03-19 | Rotta Research Laboratorium S.P.A. | Amidic derivatives of glutamic, aspartic and 2-amino adipic acids, a process for preparing same, and anti-gastrin composition containing the derivatives |
US5602179A (en) * | 1987-02-05 | 1997-02-11 | Rotta Research Laboratorium S.P.A. | Optically-active derivatives of (R) 5-pentylamino-5-oxopentanoic acid with antagonistic activity towards cholecystokinin and a method for their preparation |
US5716958A (en) * | 1994-10-27 | 1998-02-10 | Tobishi Pharmaceutical Co., Ltd. | Amino acid derivative having anti-CCK activity |
WO1999018967A1 (en) * | 1997-10-15 | 1999-04-22 | Panos Therapeutics Limited | Analgesic compositions |
US20120053243A1 (en) * | 2003-11-27 | 2012-03-01 | Shiseido Company, Ltd. | Parakeratosis inhibitor and skin preparation for external use |
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Families Citing this family (7)
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IT1215169B (en) * | 1985-12-17 | 1990-01-31 | Rotta Research Lab | OXYGENATED ALCHYL DERIVATIVES OF GLUTAMIC AND ASPARTIC ACIDS WITH ANTAGONIST ACTIVITY ON BIOACTIVE POLYPEPTIDES AND PROCEDURE FOR THEIR PREPARATION |
US4880938A (en) * | 1986-06-16 | 1989-11-14 | Merck & Co., Inc. | Amino acid analogs |
US5089638A (en) * | 1986-06-16 | 1992-02-18 | Merck & Co., Inc. | Amino acid analogs as CCK-antagonists |
IT1196849B (en) * | 1986-12-16 | 1988-11-25 | Rotta Research Lab | NEW DERIVATIVES OF ACIDS 5 PENTILAMINO 5 OXO PENTAOIC AND 4 PENTILAMINO 4 OXO BUTANOIC WITH ANTAGONIST ACTIVITY OF THE CHOLECYSTOKININ AND PROCEDURE FOR THEIR PREPARATION |
US4971978A (en) * | 1987-09-21 | 1990-11-20 | Nadzan Alex M | Derivatives of D-glutamic acid and D-aspartic acid |
EP0436612A4 (en) * | 1988-09-30 | 1992-05-20 | Australian Commercial Research & Development Limited | Amino acid transport proteins, amino acid analogues, assay apparatus, uses thereof for treatment and diagnosis of cancer |
FR2643371B1 (en) * | 1989-02-17 | 1993-11-05 | Roussel Uclaf | NOVEL 2-AMINO PENTANEDIOIC ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
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US3551419A (en) * | 1964-07-31 | 1970-12-29 | Rotta Research Lab | Amino acid amides and process for their production |
JPS4914421A (en) * | 1972-06-07 | 1974-02-07 |
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US2828327A (en) * | 1953-12-17 | 1958-03-25 | Monsanto Chemicals | Esters of n-aroylaspartic acids |
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1985
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- 1985-06-17 NZ NZ212436A patent/NZ212436A/en unknown
- 1985-06-18 CA CA000484341A patent/CA1325633C/en not_active Expired - Fee Related
- 1985-06-18 US US06/746,065 patent/US4791215A/en not_active Expired - Lifetime
- 1985-06-19 GB GB08515555A patent/GB2160869B/en not_active Expired
- 1985-06-20 SE SE8503097A patent/SE503111C2/en not_active IP Right Cessation
- 1985-06-20 CH CH2617/85A patent/CH674203A5/it not_active IP Right Cessation
- 1985-06-20 FR FR8509383A patent/FR2566397B1/en not_active Expired
- 1985-06-21 BE BE0/215244A patent/BE902726A/en not_active IP Right Cessation
- 1985-06-22 ES ES544462A patent/ES8604859A1/en not_active Expired
- 1985-06-24 AT AT0186985A patent/AT390949B/en not_active IP Right Cessation
- 1985-06-24 DE DE19853522506 patent/DE3522506A1/en active Granted
- 1985-06-24 DK DK285685A patent/DK285685A/en not_active Application Discontinuation
- 1985-06-24 AU AU44109/85A patent/AU566601B2/en not_active Ceased
- 1985-06-25 NL NL8501829A patent/NL8501829A/en not_active Application Discontinuation
Patent Citations (2)
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US3551419A (en) * | 1964-07-31 | 1970-12-29 | Rotta Research Lab | Amino acid amides and process for their production |
JPS4914421A (en) * | 1972-06-07 | 1974-02-07 |
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US5602179A (en) * | 1987-02-05 | 1997-02-11 | Rotta Research Laboratorium S.P.A. | Optically-active derivatives of (R) 5-pentylamino-5-oxopentanoic acid with antagonistic activity towards cholecystokinin and a method for their preparation |
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EP0411668A3 (en) * | 1989-08-04 | 1992-01-29 | Warner-Lambert Company | Central cholecystokinin antagonists for treatment of psychiatric disorders |
EP0727215A2 (en) * | 1989-08-04 | 1996-08-21 | MERCK SHARP & DOHME LTD. | Central cholecystokinin antagonists for treatment of psychiatric disorders |
US5550126A (en) * | 1989-08-04 | 1996-08-27 | Merck Sharp And Dohme Limited | Central cholecystokinin antagonists having pharmaceutical activity |
EP0727215A3 (en) * | 1989-08-04 | 1996-11-06 | Merck Sharp & Dohme | Central cholecystokinin antagonists for treatment of psychiatric disorders |
US5399748A (en) * | 1990-07-12 | 1995-03-21 | James Black Foundation Limited | Derivatives of aspartic acid and glutamic acid having anticholecystokinin activity |
US5500430A (en) * | 1990-12-11 | 1996-03-19 | Rotta Research Laboratorium S.P.A. | Amidic derivatives of glutamic, aspartic and 2-amino adipic acids, a process for preparing same, and anti-gastrin composition containing the derivatives |
US5153191A (en) * | 1991-08-20 | 1992-10-06 | Warner-Lambert Company | Cholecystokinin antagonists useful for treating depression |
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US11964929B2 (en) | 2018-12-18 | 2024-04-23 | Wisorig Technologies Pte. Limited | Application of glutamine derivative in preparation of animal feed additive |
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Also Published As
Publication number | Publication date |
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IE851502L (en) | 1985-12-22 |
NZ212436A (en) | 1989-04-26 |
DE3522506A1 (en) | 1986-01-02 |
GB2160869B (en) | 1988-03-16 |
CH674203A5 (en) | 1990-05-15 |
SE8503097L (en) | 1985-12-26 |
AU4410985A (en) | 1986-01-02 |
DK285685D0 (en) | 1985-06-24 |
BE902726A (en) | 1985-10-16 |
GB8515555D0 (en) | 1985-07-24 |
SE503111C2 (en) | 1996-03-25 |
FR2566397A1 (en) | 1985-12-27 |
SE8503097D0 (en) | 1985-06-20 |
ES544462A0 (en) | 1986-03-16 |
DE3522506C2 (en) | 1988-03-10 |
AT390949B (en) | 1990-07-25 |
IE57892B1 (en) | 1993-05-05 |
ATA186985A (en) | 1990-01-15 |
DK285685A (en) | 1985-12-26 |
GB2160869A (en) | 1986-01-02 |
ES8604859A1 (en) | 1986-03-16 |
CA1325633C (en) | 1993-12-28 |
FR2566397B1 (en) | 1988-08-05 |
NL8501829A (en) | 1986-01-16 |
AU566601B2 (en) | 1987-10-22 |
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